Twenty-eight percent of patients that require mechanical ventilation for more than 2 days develop a new depressive disorder within two months. Preventing depression would likely improve the health, rehabilitation and quality of life for the approximately half-million Americans that annually survive respiratory failure and prolonged mechanical ventilation. In human studies and analogous animal models, depression can be substantially prevented if antidepressant medications are given during the period of inflammatory or environmental stress. This leads to our hypothesis that depression can be prevented by early administration of SSRI medications to patients with acute respiratory failure thereby accelerating their return to best possible function. However, the barriers to conducting a large, multi-center depression prevention trial in critically ill humans are significant. Conducting a smaller feasibility study is a logical first step. Therefore, the objective of this revised R34 application by a new investigator with research experience in critical care medicine and psychiatry is to establish the feasibility of conducting a large-scale randomized trial to administer escitalopram to patients very early in the course of acute respiratory failure. A randomized, double-blind, placebo-controlled, single-site primary prevention trial with a scheduled dose escalation is proposed to determine if it is feasible to rapidly identify eligible subjects;obtain a high proportion of consent (>60%) from proxies;enroll 100 subjects over 2 years;administer at least 80% of planned doses;have >90% 8 week follow-up and successfully mask active medication assignment. The trial will also determine the proportion of subjects that decline re-consent, use off-protocol antidepressants or develop antidepressant withdrawal symptoms. Medical adverse event and suicidal ideation rates will be recorded. While the modest sample size precludes definitive hypothesis testing of differences in depression scores or adverse event rates between the experimental arms, these data will be used to estimate design parameters and to select a primary depression measure for a subsequent effectiveness trial. This application is responsive to NIMH PAR-06-248 From Intervention Development to Services: Exploratory Research Grants and addresses two priority areas in the NIMH Strategic Plan on Mood Disorders Research. The interdisciplinary research team includes a critical care clinician and researcher, psychiatrist, bioethicist, research subject advocate and a clinical trialist.